The invention concerns a medicine for the transdermal delivery of (R)-3,3-diphenylpropylamine-monoesters as well as their application for the manufacture of a medicine for transdermal delivery.
The proportion of seniors within the total population has gone up significantly in the past 50 years. Bladder dysfunctions belong to the most common geriatric diseases in this group. Therefore, ever greater and more specific significance is being attached to the development of a most effective and gentle treatment of bladder complaints.
In the case of urge incontinence the dysfunction lies in a malfunction of the bladder muscle. Frequently the cause is a stimulation or more precisely a hyperactivity of the muscarinic receptors. For this reason use of the antimuscarinic active ingredients Tolterodin and Oxybutynin is preferred for the treatment of the hyperactive bladder and the associated symptoms such as increased urinary urgency, abnormally frequent micturation or nocturia.
However, Oxybutynin is an effective antimuscarinic active ingredient that has serious side effects. Notably the pronounced dryness of the mouth is felt by many patients to be extremely unpleasant.
By comparison with Oxybutynin Tolterodin appears to exhibit lower rates of muscarinic side effects. In an organism Tolterodin is predominantly dealkylated into active main metabolites 2-[3-(1,1-diisopropylamino)-1-phenylpropyl]-4-(hydroxy methyl)phenol by the cytochrome P450-isoenzyme 2D6 as well as—slowly—into inactive metabolites by the cytochrome P 450 isoenzyme 3A4.
Since Tolterodin is metabolized exclusively by the P450-isoenzyme, there is the potential danger of interactions with the breakdown of other active ingredients, for example, with Warfarin (Colucci, Annals of Pharmacotherapy 33, 1999, 1173), antimycotics such as Ketoconazol (Brynne, Br J Clin Pharmacol 48, 1999, 564) macrolide antibiotics or protease inhibitors. This danger is present particularly in the case of the so-called slow metabolizers, which have a lack of 2D6, metabolize Tolterodin exclusively through 3A4 and exhibit a distinctly increased Tolterodin concentration in plasma.
WO 99/58 478 describes new derivates of 3,3-diphenylpropylamines as active muscarinic ingredients. The disclosed 3,3-diphenylpropylamine-derivates are prodrugs from 2-[3-(1,1-diisopropylamino)-1-phenylpropyl]-4-(hydroxy methyl)phenol and are hydrolyzed by esterases upon entering through biological membranes as well as in plasma. For this reason the 2D6-dependent degradation device does not apply.
In contradistinction to Tolterodin such 3,3-diphenylpropylamine derivates, for example, 2-[3-(1,1-Diisopropylamino)-1-phenylpropyl)-4-(hydroxy methyl)phenyl isobutyrate (INN: fesoterodine), therefore do not show a tendency towards accumulation even in the case of slow metabolizers, they do not interfere with P450 inductors/inhibitors and they possess an advantageous safety profile with regard to potential interactions of active ingredients and accumulation of active ingredients.
Therefore, the need arose to make the advantages of the 3,3-diphenylpropylamine derivate described in WO 99/58478, particularly the advantages of the fesoterodine, available to the collective of patients. The metabolism method of Tolterodin and the disadvantages of Oxybutynin (dry mouth) alone make clear the medical need for a medicine that does not exhibit the disadvantages of both of the previously named substances.
3,3-diphenylpropylamine monoesters may be present as stabile crystalline salts. fesoterodine-hydrogen fumarate is an example preferred for this purpose. Salts of this sort are described in WO 01/35957 and are particularly suited for oral or parenteral treatment of the hyperactive bladder.
Even though oral administration of these compounds represents an appropriate form of presentation for most patients, there is a need for an alternative form of administration. This need results not least at the old ages of the patients affected by dysfunctions of bladder motility, in which cases an array of reasons are able to speak against the oral administration of the drugs.
There is frequently a multimorbidity within this collective of patients, whereby as a general rule the patients are taking several different medications. Avoidance of passage through the intestine and the first liver passages and consequently a non-oral form of administration are frequently desirable to prevent interactions with the resorption of other drugs and/or not to burden the gastro-intestinal tract as well as the liver with additional drugs.
In addition, a number of older patients have problems with swallowing the solid forms of drugs, while other geriatric patients exhibit impaired gastrointestinal absorption, for example, as a result of acute or chronic gastrointestinal diseases or the taking of anti-infectives.
Ultimately a more constant plasma concentration of the active substance can be achieved using a form of administration that avoids the first-pass effect of the first liver passage and that also exhibits a retarding effect, which in general simultaneously leads to a lowering of the danger of undesired side effects, dryness of the mouth in particular, with unaltered or even improved clinical effectivity.